The primary problem in organ transplantation today is the shortage of human donors. A proposed solution is the use of pigs, but the risk of rejection is currently too great. The ultimate goal for transplant recipients is development of specific immune tolerance. They would then accept their grafts as "self' without immune suppression. Although tolerance is naturally induced in fetuses, it is difficult to induce in adults. A novel approach, called "surrogate tolerogenesis", would make patient's lymphocytes tolerance to a xenograft, within the fetal animal donor, and subsequently transfer them back. This permits adults to take advantage of the fetal environment. Preliminary studies induced high titers of specific human suppressor cells within fetal pigs. This preclinical proposal will assess the feasibility of surrogate tolerogenesis to prolong xenograft survival. The aims are to: 1. Establish if surrogate tolerogenesis reduces the titer of natural antibodies to pig endothelium. 2. Establish the in vivo effect of suppressor cells on the cellular immune response to the surrogate donor and the induction of pig->sheep chimerism. 3. Evaluate surrogate tolerogenesis for prolongation of pig kidney xenografts survival in sheep. A commercial organ bank could provide surgeons with tolerant lymphocytes and the corresponding pig for organ xenografts. PROPOSED COMMERCIAL APPLICATION: This technology could make xenotransplantation feasible, preventing acute rejection of pig organs without aggressive immune suppression. A commercial organ bank would provide the tolerant human lymphocytes and pig for transplantation. The technology would be applicable for kidney, pancreatic islets, heart, liver, lungs, and other organs.